Short, intense treatment for latent tuberculosis may be the wave of the future for people also infected with HIV, researchers reported.

Action Points

Explain that a study in HIV-infected adults found three-month regimens with rifapentine-isoniazid or rifampin-isoniazid were as effective as six months of isoniazid or up to six years of continuous isoniazid in preventing active TB.

Note that by contrast in a separate study, pre-exposure isoniazid was not effective in preventing TB in young children, whether or not they were HIV-infected; both studies were conducted in South Africa where both TB and HIV are prevalent.

Short, intense treatment for latent tuberculosis may be the wave of the future for people also infected with HIV, researchers reported.

In a randomized controlled trial, two short, three-month regimens prevented active TB just as well as the standard six-month course of daily isoniazid (Nydrazid, Tubizid), according to Richard Chaisson, MD, of the Johns Hopkins University School of Medicine, and colleagues.

A fourth approach – daily isoniazid for up to six years – had similar outcomes, Chaisson and colleagues reported in the July 7 issue of the New England Journal of Medicine.

Disappointingly, however, a separate study in the journal found that using isoniazid to prevent TB in children had no effect, whether they were HIV-positive or not.

Taken together, the studies suggest that a cycle of continuing transmission and reinfection is likely to make large benefits from prevention strategies "elusive," according to Edward Nardell, MD, of Harvard Medical School, and Gavin Churchyard, MD, PhD, of the London School of Hygiene and Tropical Medicine.

In an accompanying editorial, Nardell and Churchyard argued that transmission and reinfection is a fundamental and not fully appreciated obstacle to effective TB prevention in high-prevalence settings.

Better control of transmission "can best be achieved by intensified case finding, rapid diagnosis, and prompt institution of effective therapy," they wrote.

In particular, new technology now allows a diagnosis within hours, which should speed up the treatment process, always assuming, they noted, "that treatment programs are in place."

Chaisson and colleagues, however, argued that shorter, easier-to-use regimens may have an impact, even if the rates of disease in this study were equivalent.

"Simpler regimens will substantially increase the number of people receiving therapy," Chaisson said in a statement.

In their study, Chaisson and colleagues enrolled 1,148 South Africans who had HIV and a positive tuberculin skin test in one of four treatment arms:

Or standard therapy with isoniazid at 300 mg a day for six months – the control group

Patients in the study could not be on antiretroviral therapy because the rifamycins – rifapentine and rifampin – break down protease inhibitors in the liver, making them less effective as HIV treatment. However, other types of anti-HIV drugs are compatible with the rifamycins, the researchers noted.

Patients in the trial were adults, with a median age of 30, and had an average CD4-positive T-cell count of 484 per cubic millimeter. The primary outcome of the trial was tuberculosis-free survival.

After a median follow-up of about four years, with slight differences among the arms, the researchers found the incidence of active TB was not significantly different regardless of therapeutic strategy.

Specifically, the rate of active TB per 100 person-years was:

3.1 in the rifapentine-isoniazid group

2.9 in the rifampin-isoniazid group

2.7 in the continuous-isoniazid group

And 3.6 in the control group.

Adverse events in the three experimental arms were also not significantly different from those seen in the control arm, Chaisson and colleagues reported.

The study in children randomly assigned 548 HIV-positive and 804 HIV-negative infants – ages 91 to 120 days -- to isoniazid at 10 to 20 mg per kilogram of body weight per day or to a matching placebo for 96 weeks, according to Shabir Madhi, MD, PhD, of the Respiratory and Meningeal Pathogens Research Unit in Bertsham, South Africa, and colleagues.

The primary outcome of the study was active TB and death in HIV-infected children and latent TB infection, active TB, and death in HIV-uninfected children within 96 to 108 weeks of randomization, Madhi and colleagues reported.

Most of the HIV-positive children – some 98.9% -- started antiretroviral therapy during the study, they reported. All children were given the bacille Calmette-Guérin vaccine against TB within 30 days of birth.

Isoniazid has been shown to prevent progression to active TB in children who were in contact with people with infectious tuberculosis, the researchers noted, but it has not been tested as pre-exposure prophylaxis.

Disappointingly, it did not appear to work, Madhi and colleagues reported:

In the HIV-positive children, TB disease or death occurred in 52 children in the isoniazid group and 53 in the placebo group. The difference -- 19% versus 19.3% -- was not significant.

Among HIV-uninfected children, 39 children in the isoniazid group and 45 in the placebo group met the combined endpoint of TB infection, TB disease, or death. The difference – 10% versus 11% -- was again not significant.

The incidence of TB was 121 cases per 1,000 child-years among the HIV-positive children, compared with 41 per 1,000 child-years in the HIV-uninfected children. The 95% confidence intervals did not overlap.

There were no significant differences in clinical or severe laboratory toxic effects.

The rifapentine study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Chaisson did not report any conflicts.

The isoniazid study was supported by the the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and the Secure the Future Fund, a philanthropy program sponsored by Bristol-Myers Squibb. Madhi reported financial links with Pfizer, Novartis, and GlaxoSmithKline.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.